PF-04691502 (CAS 1013101-36-4) is a selective catalytic inhibitor targeting both PI3K and mTOR kinases, developed within Pfizer drug discovery programs and characterized by sub-nanomolar potency across the PI3K/AKT/mTOR axis. Its dual-target profile has driven broad investigation across oncology indications in preclinical models and early clinical trials. Enamine supplies PF-04691502 as an analytically validated compound for signal transduction and cancer biology research.
PF-04691502 molecular formula is C₂₂H₂₇N₅O₄ with a molecular weight of 425.48 g/mol. The PF-04691502 molecular structure is built around a pyrido[2,3-d]pyrimidine core carrying an amino group at C-2 and a methyl substituent at C-4, linked at N-8 to a trans-4-(2-hydroxyethoxy)cyclohexyl group and at C-6 to a 6-methoxypyridin-3-yl moiety. This architecture enables tight engagement of the conserved ATP-binding cleft shared by class I PI3K isoforms and mTOR. The PF-04691502 SMILES string is referenced in virtual screening and kinase selectivity profiling workflows. Registered under CAS 1013101-36-4, the compound reached Phase 1 clinical evaluation through PF-04691502 Pfizer oncology programs.
Application of PF-04691502
Research applications of PF-04691502 span colorectal, breast, ovarian, and head and neck cancers, as well as chronic lymphocytic leukemia. The compound is particularly relevant for investigating how simultaneous PI3K and mTOR blockade affects tumor cell survival, directional migration, and chemotherapy resistance. Scientists incorporate it into combination regimens alongside MEK pathway inhibitors, hormone receptor antagonists, and cytotoxic agents to map cooperative mechanisms of tumor suppression.
In Vitro
Phosphorylation of Akt at T308 and S473 is reduced by PF-04691502 with IC₅₀ values of 7.5 nM and 3.8 nM, respectively. In primary CLL isolates, treatment drives upregulation of Noxa and Puma, producing substantial cell death regardless of protective microenvironmental cues. PIK3CA-mutant colorectal cancer spheroids lose both proliferative and self-renewal capacity upon pathway blockade. Notably, sub-cytotoxic concentrations are sufficient to normalize p27 phosphorylation and suppress directional tumor cell migration.
In Vivo
Oral administration of PF-04691502 in PIK3CA-mutant colorectal xenograft models yields significant tumor growth delay at well-tolerated doses. In the Eµ-TCL1 CLL mouse model, systemic leukemia burden decreases across bone marrow, spleen, peripheral blood, and lymph nodes following treatment. Separate breast cancer studies show that low-dose regimens selectively reduce skeletal metastatic colonization without measurable effects on primary tumor proliferation.
Biochemical and Physiological Actions
PF-04691502 engages the ATP-binding site present in both PI3K catalytic subunits and the mTOR kinase domain, blocking signal propagation through the entire PI3K/AKT/mTOR cascade. Crucially, mTORC2 co-inhibition eliminates the AKT reactivation feedback that limits the efficacy of mTORC1-only agents, resulting in durable suppression of p-AKT, p-S6K, and p-4EBP1. The absence of compensatory mTORC2 signaling makes PF-04691502 particularly suited for clean mechanistic dissection of pathway dependencies in tumor models.
Features and Benefits of PF-04691502
PF-04691502 (CAS 1013101-36-4) combines mechanistic clarity with broad experimental utility across cancer research:
- sub-nanomolar Akt phosphorylation suppression (IC₅₀ 3.8–7.5 nM) without compensatory mTORC2 reactivation;
- efficacy demonstrated across leukemia, solid tumor, and cancer stem cell model systems;
- clinical Phase 1 and Phase 2 datasets available to support translational study design;
- well-defined PF-04691502 molecular structure enabling structure-activity and combination research.
When sourced as EBC-221078, the compound meets analytical quality standards required for reproducible biochemical and cellular assay workflows.
